Toxic actions of the neurotransmitter, glutamic acid, have been implicated in a number of diseases that effect the brain including stroke, epilepsy, Huntington~s disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. These toxic actions of glutamate are mediated through the same neurotransmitter receptors on nerve cells that ordinarily serve to convey glutamate's excitatory signal to nerve cells. Recent experimental evidence suggests that some subtypes of metabotropic glutamate receptors may attenuate glutamate excitotoxicity while other subtypes of metabotropic glutamate receptors aggravate excitotoxicity. In addition, drugs that specifically bind to the different subtypes of metabotropic receptors have been invented recently. This project will use molecular pharmacologic techniques to better define the role of metabotropic glutamate receptors in excitotoxic and metabolic death of nerve cells. A combination of stereotaxic lesions, pharmacological manipulations, quantitative morphometry and in situ hybridization histochemistry will be used to test the hypothesis that metabotropic receptors linked to the phosphatidyl inositol second messenger system aggravate while metabotropic receptors linked to the adenylate cyclase second messenger system attenuate excitotoxicity. Injections of antisense messenger RNA to specifically block synthesis of the different metabotropic receptors will be used to further define the roles of the different metabotropic receptors.